Clinical modification of undesirable animal behaviors exhibited by household domesticated pets using psychopharmacological agents is a relatively new phenomenon in veterinary medicine and today is a most-poorly understood therapy among practicing veterinarians. Prior to about 1974, the veterinary science of modifying specific animal behaviors was in its most rudimentary stages; and the idea of pharmacologically treating specific behavior problems in domesticated animals or household pets was in its infancy. Subsequently, between about 1974-1984, such animal behavior modification methods as existed focused primarily upon behavioral shaping techniques developed from the science of ethology, the study of innate animal behavior patterns; and employed conditioning strategies to elicit behavior modifications in the animal. Thus, the use of pharmacologically active substances to control or modify undesired animal behaviors was only just being explored in the mid-1980s as a most radical and suspect approach by practicing veterinarians. Moreover, after 1985 and continuing even to date for most veterinarians, the idea of administering psychopharmacological agents to household pets as a means for clinically modifying undesirable animal behaviors was and remains directly comparable and analogous to the skepticism of clinicians and attending physicians of about 1950 who found the concept of treating humans exhibiting behavioral disorders with psychopharmacological drugs to be a rash and unwholesome idea.
Within this analogous historical context, therefore, it is most valuable to review summarily the nature of human aggression behaviors, their underlying psychological mental disorders, and the development of psychopharmacological methods for controlling acts of human aggression. Human acts performed with the deliberate intent of causing physical harm to persons or property are, by definition, human aggression and have a wide range of causative factors. Moreover, human aggression behaviors and human acts of violence are considered symptoms rather than diseases and are most frequently associated with an underlying psychological disorder rather than a medical condition. Thus depression, schizophrenia, personality disorders, mania, paranoia, temporal lobe dysfunction, and the consequences of substance abuse each may be the underlying disorder associated with one or more specific acts of human aggression. [Current Medical Diagnosis & Treatment 1995 Tierney, McPhee and Papadakis, editors, Appleton & Lange, Norwalk, Conn.; Maxmen, J. S. and N. G. Ward, Essential Psychopathology And Its Treatment, Second edition, W. W. Norton & Co., 1995.]
It is also noteworthy that human psychopharmacology as a science and the continuing search for the origins and mediators of human aggression behaviors in its many different forms and varieties have been related areas of investigation since the late 1940s. Clinical concerns with treating highly aggressive human individuals were initially and remain today a starting point for inquiries into the range of neurobiological mechanisms that cause, mediate, or control human aggressive behavior patterns; and, within the clinical setting, human aggression is seen as an abnormality, a psychopathological or sociopathological behavior pattern that requires therapeutic treatment.
Human psychopharmacology and human neuropharmacology in particular have evolved and developed in major part as a response to the ongoing need for a range of different agents which can be used in the treatment of diverse pathological aggressive behaviors or for controlling the differing symptoms of aggression and hostility that are part of the human pathological behavioral disorders. A host of human affective mental disorders (including mood disorders such as major depression and bipolar mania and psychotic disorders such as schizophrenia) often include violent behaviors and aggressive outbursts which may be treatable using particular classes of psychopharmacological drugs. In comparison, pathological aggressive behavioral acts based upon neural mechanisms or the intense aggressive behavior exhibited in the course of human addiction to and withdrawal from narcotics-each may require very different classes of psychopharmaceutical agents as therapeutic treatments [Yudofsky et. al., Psychiatric Annals 17:397-407 (1987)].
Many different forms of human aggressive behavior are individually known and well characterized either by reports of personal case medical histories or by human experimental-psychological group studies. Due to ethical considerations, however, humans are not suitable candidates for clinical or research experimentation. For these reasons, experimental procedures and settings were designed during the 1960s and 1970s for the purpose of generating a range and variety of animal models which might be representative and illustrative of specific types or selected examples of human aggressive behaviors and/or serve as an indicator for the underlying root causes and mediators of human aggressive behaviors. Thus, almost every major class of psychopharmacological drugs intended for human usage has been investigated in different animal models, each representative of a specified type of human aggressive behavior. These models were conducted mainly in isolated mice and rats that were exposed to pain or other stimuli, but also utilized fish, pigeons, cats and primates as representative subjects. [See for example: Sheard, M. H., "Animal Models Of Aggressive Behavior" in Animal Models In Psychiatry And Neurology, Pergamon Press, Oxford, 1977, pp. 247-257; Eichelman, B., "Animal models: Their role in the aggressive behavior of humans", Progr.. Neuro-Psychopharmacol. 2:633-643 (1978); and Miczek, K. A., "The Psychopharmacology Of Aggression" in HANDBOOK OF PSYCHOPHARMACOLOGY, Vol. 19, Plenum Publishing Corp., 1987, Chap. 4, pp. 183-328 and the references cited therein.]
A summary review of the various types or categories of different animal models often used as representative examples of human aggression behaviors provides insight and understanding as to their intrinsic limitations and substantive restrictions. One animal model experimental design employs exposure to aversive living conditions to engender aggressive behavior. In these model experiments, deprivation of social contact, or crowding and restricted access to limited resources such as food, or the presentation of aversive external stimuli such as electric shock pulses and omission or intermittency of scheduled reinforcement--are used as artificial and experimental manipulations to intentionally induce and elicit aggressive behaviors in the test animals. All of these are environmental manipulations and are usually performed upon placid and domesticated laboratory animals which rarely, if ever, exhibit aggressive behavior. Thus, in this animal model system, to evoke or induce an act of aggression by intentionally exposing an otherwise non aggressive animal subject to aversive environmental stimuli has led to the often expressed view that aggressive behavior represents an antisocial response. [See for example: Malick, J. B., Curr. Der. Psychopharmacol. 5:1-27 ( 1979); Oliver et. al., Psychopharmacoloqy 97:154-156 (1989); Krsiak, M., Res. Commun. Chem. Path. Pharmacol. 7:253-257 (1974); Oliver, B. and D. von Dalen, Aggress. Behav. 8:163-168 (1982).]
Another animal model of human aggressive behaviors begins with the premise that every living species (human or animal) that can fight will fight, given the appropriate conditions. Thus, in this animal model system, an attack toward a territorial intruder or towards an unfamiliar group member; or a defense of one's young; or the competition for preferred food, mates, and niches of living; or a threat in the context of change in group formation and social standing--all are aggression provoking situations. These diverse types or forms of aggressive behaviors have collectively been termed "agonistic behaviors" in order to capture under one general heading the many different behavior elements typically encountered among these diverse conflict situations. [See for example: Scott, J. P., Aggression, University of Chicago Press, 1958; Scott, J. P., Am. Zoologist 6:683-701 (1966); Dixon, A. K. and H. P. Kaesermann, "Ethopharmacology of flight behavior," in Ethopharmacology Of Agonistic Behavior In Animals And Humans, Martinus Nijhoff, Dordrecht, 1987, pp. 46-70.]
A third kind of animal model system uses direct electrical or chemical stimulation of neural foci to evoke sequences of attack and defense behaviors as well as predatory attack in several animal species. In this model system, electrical neuronal activity is detected and often recorded; and the brain stimulation evoked aggressive or defensive behaviors exhibited by the animals is said to parallel in many respects the animal behavior seen in the wild or under natural conditions. [See for example: Siegel et. al., Brain Res. 93:473-484 (1975); Yamamoto et. al., Jpn. J. Pharmacol. 29:(Supp) 41P (1979); Conner e.t., al., Physiol. Behav. 5:1221-1224 (1970).]
In addition, as human aggressive behaviors became increasingly recognized as being of differing types and causes; and that a single type of human aggressive behavior may be pathological, or antisocial; the reported scientific investigations of neural mechanisms of action for aggression and therapeutic agent interaction have generated highly varied differences and sometimes even contradictions in information and knowledge. These reported experimental differences, empirical discrepancies, evidentiary inconsistencies, and conclusionary contradictions are often the consequence of intrinsic differences in the overall investigative strategy chosen for use. Traditionally, two different investigative strategies have been pursued. A first type (I) of research study uses drugs as tools for identifying and characterizing the neural mechanisms that might underlie a specific kind of aggressive behavior. This first type (I) assumes that the mechanism of drug action is well understood; and thus the experimental results are a direct reflection and consequence of specific drug interactions--a questionable premise. Alternatively, the second type (II) of investigative strategy employs specific aggressive acts as a means to screen for evaluating a novel compound or class of drugs; or to serve as markets for a specific neurotransmitter, a specific neurotransmitter activity, or a neurotransmitter receptor protein. The underlying premise and assumption of these second type (II) investigations is that the selected aggressive behavior and its neural basis are known, well understood, and adequately described in the literature.
Unfortunately, it is generally now appreciated that the in-vivo mechanisms for even the simplest aggressive act and behavior are very complex and incompletely understood. Any type of aggression and aggressive behavioral action must be carefully characterized and individually distinguished as to specific origin, type and nature. The scientific literature is replete with reviews and classification frameworks describing, separating, and distinguishing among the many forms of behavioral aggression. Merely representative of such publications are the following, the texts of which are each expressly incorporated by reference herein: Maxmen, J. S. and N. G. Ward, Essential Psychopathology And Its Treatment, Second edition, W. W. Norton & Co., 1995; HANDBOOK OF PSYCHOPHARMACOLOGY (Iversan et. al., editors), Vol. 19, 1987, Plenum Publishing Corp., Chap. 4, pp. 183-328; Drews, C., "The Concept And Definition Of Dominance In Animal Behavior", Behavior 125:286-313 (1993); Miczek, K. A. and P. Donat, "Brain 5-HT System And Inhibition Of Aggressive Behavior", in BEHAVIORAL PSYCHOPHARMACOLOGY OF 5-HT (Bevan, Cools & Archer, editors), 1989, Lawrence Erlbaum Associates, Chap. 10, pp. 117-144].
Equally important today in understanding properly the behavioral complexities of aggression behaviors and aggressive interactions is the now generally discredited theory and erroneous view that modifications of a single neurotransmitter might yield meaningful changes in aggressive behavior. It is important to note that at varying times in the history of this technological field, each of the known endogenous biogenic amines present in the brain and/or neural tissue was suspected of being the critical "code" or key to controlling and modifying aggressive behavior. Thus, in turn, the "aggressive monoamines" [Eichelman et. al., Pharmacol. Blochem. Rev. 1:121-123 (1973)], hypothalamic acetylcholine [Smith et. al., Science 167:900-901 (1970)], and serotonin [Valzelli. L. and S. Grattini, Adv. Pharmacol. 6B: 249-260 (1968)] each were offered and wrongly presented as being mediators in the control of all aggressive behavior. About 1970, the single neurotransmitter theory of control was expanded initially to a "neurochemical dualism" and then eventually increased to a theory of multitransmitter control of aggressive behaviors. [See for example: Reis, D. J., "The chemical coding of aggression in brain" in Neurohumoral Coding Of Brain Function, 1974, Plenum Press, pp. 125-150; Avis, H. H., Psychol. Bull. 81:47-63 (1974); Pradhan, S. N., "Aggression And Central Transmitters" in International Review Of Neurobiology, 1975, Academic Press, p. 213; Daruna, J. H., Neurosci. Biobehav. Rev. 2:101-113 (1978)]. Within these theories, just as a nerve cell membrane may either be excited or inhibited at the cellular level, aggressive behavior was wrongly believed to be under the excitatory and inhibitory control by functionally opposite neurotransmitters. The candidates for such behavioral excitation were initially thought to be norepinephrine and acetylcholine, which were later supplanted by dopamine and serotonin. This concept of exciting and inhibiting aggressive behavior by opponent neurotransmitters is seen today as overly simplistic and unable to account for the origins, range, and diversity of aggressive human behaviors as well as failing to explain or account for the behavioral complexities of aggressive interactions among members of the same species, much less between individuals of different species. [See for example: Miczek, K. A., "The Psychopharmacology of Aggression," in Handbook of Psychopharmacology, (Ivarsan et. al., editors), Plenum Pub. Co., Vol. 19, 1987, Chap. 4, pp. 183-328 and the references cited therein. ]
With the complete discrediting of the "code" neurotransmitter theories for controlling all human aggression behaviors generally, the recent trends of research investigations and psychopharmacological experimentation in this field have begun to explore what might be the actual function of the various endogenous neurotransmitters and the true nature of their interactions in specific kinds of human aggressive behaviors, often using carefully selected animal models representative of a specific type of human aggression. These more recently published reports have typically followed one of two different investigative themes: Evaluations of active neurotransmitters and/or neurotransmitter metabolites in living human patients suffering from specific and well characterized forms of aggression; and purposeful challenges of neurotransmitters and/or their receptors within selected animal models putatively representative of a specific human aggressive behavior.
Exemplifying the investigations of neurotransmitters and their metabolites within human patient pools exhibiting a specified form of aggressive behaviors are the following publications: Serotonin in obsessions, compulsions and aggressive impulses of man [Insel et. al., Ann. N.Y. Acad. Sci. 487:574-582 (1987)]; biological correlates of suicidal risk and aggressive behavior traits in man [Linnoila, M. and M. Virkkunen, J. Clin. Psychopharmacol. 12:19S-20S (1992)]; central serotonin and impulsive aggression in man [Coccaro, E. F., Brit. J. Pysch. 155:52-62 (1989)]; serotonin, suicide, and aggression in man [Golden et. al., J. Clin. Psych. 52:61-69 (1991)]; relationships between central and peripheral serotonin indexes in depressed and suicidal psychiatric inpatients [Mann et. al., Arch. Gen. Psychiatry 49:442-446 (1992)]; the relationship of tryptophan, 5-HIAA, and IAA to sex, age, epilepsy and anticonvulsive drugs [Young et. al, J. Neurol. Neurosurg. Psych, 43:438-445 (1980)]; CSF neurochemistry in depressed, manic and schizophrenic human patients compared to human normal controls [Gurner et. al., Am. J. Psych. 141:1533-1540 (1984)]; suicidality and 5-HIAA concentration associated with the tryptophane hydroxylase gene in man [Nielsen et. al., Arch. Gen Psychiatry 51:34-38 (1994)]; personality profiles and state aggressiveness in Finnish alcoholic, violent offenders, fire setters, and healthy volunteers [Virkkunen et. al., Arch. Gen Psychiatry 51:28-33 (1994)]; serotonin correlates of suicidal and aggressive behaviors in man [Coccaro, E. F. and R. J. Kavoussi, Neuropsychopharmacoloqy 10:726S-727S (1994)]; and the role for central 5-HT receptor function in impulsive aggressive behavior in humans [Coccaro et. al., Psychopharmacoloqy Bulletin 26:393-405 (1990)].
In comparison, the investigations of neurotransmitters, their metabolites, and chemical challenges of these within controlled animal models representative of a specific human aggression behavior are merely represented by the following publications: reconciling the role of central serotonin neurons in human and animal behavior using rats [Soubrie, P., The Behavior And Brain Sciences 9:319-364 (1986)]; relationship between dominance hierarchy, cerebrospinal fluid levels of amine transmitter metabolites (5-HIAA and homovanillic acid) and plasma control in monkeys [Yodyingyuard et. al., Neuroscience 16:851-858 (1985)]; hormone-dependent aggression in male and female rats [Albert et. al., Neurosci. Biobehav. Rev. 16:177-192 (1992)]; the increase of serotonin but not dopamine metabolites in brain regions of subordinate rats in a colony [Blanchard et. al., Brain Res. 568:61-66 (1991)]; the reversal of testosterone-induced dominance by the serotonergic agonist quipazine between male rat pairs [Bonson, K. R. and J. C. Winter, Pharmacology Biochemistry and Behavior 42:809-81 3 (1992)]; effects of monoaminergic agonists on alcohol-induced increases in mouse aggression [Wagner et. al., J. Stud. Alcohol, Supp. 11:185-191 (1993); serotonergic control of anabolic steroid-induced aggression in rats [Bonson et. al., Pharmacology Biochemistry and Behavior 49:31 3-332 (1994)]; aggressive behavior in mice lacking 5-HT.sub.1B receptor [Saudou et. al., Science 265:1875-1878 (1994)]; serotonergic mechanisms promoting dominance aggression in adult male vervet monkeys [Raleigh et., al., Brain research 559:181-190 (1991)]; prolactin responses to fenfluramine challenge in adult male cynomolgus macaques [Botchin et. al., Neuropsychopharmacology 9:93-99 (1993)]; the role of brain serotonin neurons in dominance-subordination behavior among rats [Kotowski et. al., Physiol. Behav. 33:365-371 (1984)]; and inherent and environmental factors influencing serotonergic activity and behavior in monkeys [Kaplan et. al., Neuropharmacology 10:389S (1994 )].
The historical overview presented herein thus reveals that the various animal models have been and remain today a primary research investigative tool used for the betterment of humans and human problems as well as an aid to physicians and psychiatrists in the therapeutic treatment of human pathological behavioral disorders. However, even today there is much which is not yet understood about the actions of active psychopharmacological agents and their effects upon the various forms of human pathological behavior disorders. Equally important, as limited as the comprehension is today regarding the complexity of human psychopharmacological treatments for specific forms of human aggression behaviors, the quantum of knowledge and information directed to veterinary behavioral problems and a purposeful veterinary use of psychopharmacological agents for clinically modifying a varied range of animal aggressive behaviors is far more circumscribed and far less reliable. Accordingly, the generation and clinical demonstration of an effective veterinary psychopharmaceutical treatment method clinically to modify animal affective aggression behaviors in a household pet would be viewed as an unforeseen development, unusual benefit and marked advantage by practicing veterinarians.